title: Comb-like amphiphilic copolymers bearing acetal-functionalized backbones with the ability of acid-triggered hydrophobic-to-hydrophilic transition as effective nanocarriers for intracellular release of curcumin.
abstract: The pH-responsive micelles have enormous potential as nanosized drug carriers for cancer therapy due to their physicochemical changes in response to the tumor intracellular acidic microenvironment. Herein, a series of comb-like amphiphilic copolymers bearing acetal-functionalized backbone were developed based on poly[(2,4,6-trimethoxybenzylidene-1,1,1-tris(hydroxymethyl) ethane methacrylate-co-poly(ethylene glycol) methyl ether methacrylate] [P(TTMA-co-mPEGMA)] as effective nanocarriers for intracellular curcumin (CUR) release. P(TTMA-co-mPEGMA) copolymers with different hydrophobic-hydrophilic ratios were prepared by one-step reversible addition fragmentation chain transfer (RAFT) copolymerization of TTMA and mPEGMA. Their molecular structures and chemical compositions were confirmed by (1)H NMR, Fourier transform infrared spectroscopy (FT-IR) and gel permeation chromatography (GPC). P(TTMA-co-mPEGMA) copolymers could self-assemble into nanosized micelles in aqueous solution and displayed low critical micelle concentration (CMC). All P(TTMA-co-mPEGMA) micelles displayed excellent drug loading capacity, due to the strong π-π conjugate action and hydrophobic interaction between the PTTMA and CUR. Moreover, the hydrophobic PTTMA chain could be selectively hydrolyzed into a hydrophilic backbone in the mildly acidic environment, leading to significant swelling and final disassembly of the micelles. These morphological changes of P(TTMA-co-mPEGMA) micelles with time at pH 5.0 were determined by DLS and TEM. The in vitro CUR release from the micelles exhibited a pH-dependent behavior. The release rate of CUR was significantly accelerated at mildly acidic pH of 4.0 and 5.0 compared to that at pH 7.4. Toxicity test revealed that the P(TTMA-co-mPEGMA) copolymers exhibited low cytotoxicity, whereas the CUR-loaded micelles maintained high cytotoxicity for HepG-2 and EC-109 cells. The results indicated that the novel P(TTMA-co-mPEGMA) micelles with low CMC, small and tunable sizes, high drug loading, pH-responsive drug release behavior, and good biocompatibility may have potential as hydrophobic drug delivery nanocarriers for cancer therapy with intelligent delivery.
authors.affiliation: School of Materials Science and Engineering, Tianjin University , Tianjin, 300072, People's Republic of China.
authors.forename: Junqiang
authors.initials: J
authors.lastname: Zhao
authors.forename: Haiyang
authors.initials: H
authors.lastname: Wang
authors.forename: Jinjian
authors.initials: J
authors.lastname: Liu
authors.forename: Liandong
authors.initials: L
authors.lastname: Deng
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Liu
authors.forename: Anjie
authors.initials: A
authors.lastname: Dong
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000080:Acetals / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003474:Curcumin / Q000008:administration & dosage* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry*; D004354:Drug Screening Assays, Antitumor; D056945:Hep G2 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis / Q000187:drug effects; D057927:Hydrophobic and Hydrophilic Interactions; D008823:Micelles; D015394:Molecular Structure; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D010316:Particle Size; D011108:Polymers / Q000008:administration & dosage / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013499:Surface Properties; D013501:Surface-Active Agents / Q000008:administration & dosage / Q000737:chemistry*
chemical_list: D000080:Acetals; D000970:Antineoplastic Agents; D004337:Drug Carriers; D008823:Micelles; D011108:Polymers; D013501:Surface-Active Agents; D003474:Curcumin